First Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan.
Department of Statistical Genetics, Osaka University School of Medicine Graduate School of Medicine, Suita, Osaka, Japan.
Ann Rheum Dis. 2024 Jan 11;83(2):242-252. doi: 10.1136/ard-2023-224537.
Extracting immunological and clinical heterogeneity across autoimmune rheumatic diseases (AIRDs) is essential towards personalised medicine.
We conducted large-scale and cohort-wide immunophenotyping of 46 peripheral immune cells using Human Immunology Protocol of comprehensive 8-colour flow cytometric analysis. Dataset consisted of >1000 Japanese patients of 11 AIRDs with deep clinical information registered at the FLOW study, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In-depth clinical and immunological characterisation was conducted for the identified RA patient clusters, including associations of inborn human genetics represented by Polygenic Risk Score (PRS).
Multimodal clustering of immunophenotypes deciphered underlying disease-cell type network in immune cell, disease and patient cluster resolutions. This provided immune cell type specificity shared or distinct across AIRDs, such as close immunological network between mixed connective tissue disease and SLE. Individual patient-level clustering dissected patients with AIRD into several clusters with different immunological features. Of these, RA-like or SLE-like clusters were exclusively dominant, showing immunological differentiation between RA and SLE across AIRDs. In-depth clinical analysis of RA revealed that such patient clusters differentially defined clinical heterogeneity in disease activity and treatment responses, such as treatment resistance in patients with RA with SLE-like immunophenotypes. PRS based on RA case-control and within-case stratified genome-wide association studies were associated with clinical and immunological characteristics. This pointed immune cell type implicated in disease biology such as dendritic cells for RA-interstitial lung disease.
Cohort-wide and cross-disease immunophenotyping elucidate clinically heterogeneous patient subtypes existing within single disease in immune cell type-specific manner.
从自身免疫性风湿病（AIRD）中提取免疫和临床异质性对于个性化医疗至关重要。
我们使用全面的 8 色流式细胞术分析的人类免疫学方案对 46 种外周免疫细胞进行了大规模和全队列免疫表型分析。该数据集包括来自 FLOW 研究的 11 种 AIRD 的>1000 名日本患者，这些患者具有深度临床信息，包括类风湿关节炎（RA）和系统性红斑狼疮（SLE）。对鉴定出的 RA 患者群进行了深入的临床和免疫学特征分析，包括以内生性人类遗传学代表的多基因风险评分（PRS）为代表的关联。
免疫表型的多模式聚类揭示了免疫细胞、疾病和患者群分辨率中的潜在疾病-细胞类型网络。这提供了 AIRD 之间共享或独特的免疫细胞类型特异性，例如混合性结缔组织病和系统性红斑狼疮之间的密切免疫网络。个体患者水平的聚类将 AIRD 患者分为具有不同免疫特征的几个聚类。其中，RA 样或 SLE 样聚类占主导地位，表明在 AIRD 中 RA 和 SLE 之间存在免疫分化。对 RA 的深入临床分析表明，这些患者聚类在疾病活动度和治疗反应方面存在不同的临床异质性，例如具有 SLE 样免疫表型的 RA 患者存在治疗抵抗。基于 RA 病例对照和病例内分层全基因组关联研究的 PRS 与临床和免疫学特征相关。这表明免疫细胞类型与疾病生物学有关，例如 RA-间质性肺病中的树突状细胞。
全队列和跨疾病免疫表型分析以免疫细胞类型特异性的方式阐明了单个疾病中存在的具有临床异质性的患者亚群。
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